Uric acid, terminal metabolites of purine compounds in humans, is mainly excreted by the kidney, accounting for two-thirds of total excretion. The accumulation of uric acid caused by overproduction or excretion disorders results in high levels of blood uric acid, and then leads to hyperuricemia. In the normal state of purine diet, two fasting serum blood uric acid level in different days is more than 420 μmol/L for men, and more than 360 μmol/L for women, that is known as hyperuricemia. Causes of hyperuricemia can be classified in three types: (1) increased production of uric acid, (2) poor excretion of uric acid, and (3) mixed type, such classification is useful for discovering the cause of hyperuricemia and giving the targeted treatment.
With supersaturation levels of uric acid in blood, the sodium urate begins to form crystals and deposits in synovium of joint, bursae, cartilage or other tissues. The rapid changes of uric acid levels, the release of tiny crystals caused by local trauma and changes in the coating of uric acid crystals can cause repeated and paroxysmal inflammatory response, and then induce gout. Gout refers in particular to acute arthritis and chronic tophi diseases, mainly including acute onset of arthritis, tophi formation, tophi chronic arthritis, urate nephropathy, uric acid urinary tract calculi and severe symptoms such as joint disability and renal insufficiency. In addition, gout is also associated with hypertension, metabolic syndrome, hyperlipidemia, diabetes and insulin resistance and other diseases. (Terkeltaub R A. Clinical practice. Gout [J]. N Engl J Med. 2003, 349: 1647-1655)(Schlesinger N, Schumacher H R Jr. Gort: can management be improved [J]. Curr Opin Rheumatol. 2001, 13: 240-244).
Hyperuricemia and gout that endanger human health is a severe metabolic disease. The data shows that about 5%˜12% of patients with hyperuricemia eventually develop into gout. Uric acid is material basis of hyperuricemia and gout, therefore lowering the concentration of blood uric acid can be used to prevent or treat hyperuricemia and gout, and reduce the risk of complications of hyperuricemia and gout.
Currently, there are two types of drugs used for lowering uric acid level, one type of drugs is used for inhibiting uric acid production, and the other type of drugs is used for increasing uric acid excretion.
Uric acid is derived from dietary intake and endogenous synthesis of purine, which is finally generated by the oxidation of xanthine oxidase. Therefore, xanthine oxidase is regarded as an important target for drugs as inhibitors of uric acid production. Although available drug used for inhibiting production of uric acid named Lopurin has been reported to be effective in treating hyperuricemia and various diseases caused by hyperuricemia, Lopurin also has been noted having serious side effects such as toxidrome, aplastic anemia, abnormal liver function, exfoliative dermatitis and Stevens-Johnson syndrome, etc. (Kazuhide Ogino and 2 persons, Nippon Rinsho (Japan Clinical), 2003, Vol. 61, Extra edition 1, pp. 197-201). So it is necessary to develop the drugs with high efficiency, low toxicity and little side effects.
On the other hand, about 90% of hyperuricemia is caused by reduced excretion of uric acid, and uric acid excretion by the kidneys mainly includes four processes: glomerular filtration, renal tubule and collecting duct reabsorption, renal tubule and collecting duct secretion as well as reabsorption after the secretion, and the corresponding protein is involved in each process, at last, only 8%˜12% of uric acid is excreted (Liu Ruoxia, Cang Luping, Wu Xinrong, Shangdong Medical Journal [J], 2002, 52(28)). Urate anion transporter 1 (URAT1) is a transmembrane protein disclosed by Enomoto etc., which is located in the brush border side of the renal proximal tubule epithelial cell and participates in reabsorption of uric acid in the renal proximal tubule. hURAT1, encoded by SLC22A12 gene (containing 10 exons and 9 introns) on chromosome 11q13, contains 555 amino acid residues, 12 transmembrane domains, a —NH2 terminal domain and a —COOH terminal domain located inside the cell. Studies found that SLC22A12 gene carried in renal hyperuricemia patients occurred mutation, thereby losing the ability of encoding the mature URAT1 protein, which suggested that URAT1 was the pathogenic gene for renal hyperuricemia (Enomoto, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels [J]. Nature, 2002, 417 (6887): 447-452), and URAT1 was important for uric acid reabsorption in the kidney and closely related to the regulation of blood uric acid. Thus, the compounds inhibiting activity of URAT1 can be used for promoting the excretion of the blood uric acid, and treating or preventing the diseases associated with high levels of blood uric acid, including hyperuricemia, gout, tophi, gouty arthritis, renal disorders associated with hyperuricemia, urinary calculi and so on.
It has been reported that the combination of allopurinol and uricosuric drugs is more effective than allopurinol alone in lowing serum uric acid (S Takahashi, Ann. Rheum. Dis., 2003, 62, 572-575). Thus, the combination of uricosuric drug and uric acid production inhibitor can achieve therapeutic effect which monotherapy can not achieve, and can avoid the corresponding risks, for example, momotherapy of uricosuric drugs for treating hyperuricemia of poor uric acid excretion can cause the risk of urinary calculi, whereas the combination of ricosuric drug and uric acid production inhibitor can achieve better therapeutic effect.
The drugs, inhibiting both xanthine oxidase and URAT1, will provide better therapeutic effect for patients and be more convenient than combined drugs. It has been a hot topic for treating hyperuricemia, gout and diseases associated with hyperuricemia.